Despite the wide availability of potent antiretroviral therapy, up to 50% of HIV-infected individuals continue to demonstrate milder forms of HIV-associated neurocognitive disorders (HAND). With the increasing aging population of HIV-infected patients who are at greater risk for developing HAND, the cost of care may nearly double in the next two decades. Co-morbid issues such as alcohol, marijuana or psychostimulant abuse, which occur at much higher prevalence amongst HIV patients, can further exacerbate their cognitive deficits. Since effective treatment and preventions for HAND are still lacking, developing effective treatments or adjunctive therapy for these patients are critical. Working memory (WM) and attention deficits are common and may underlie cognitive deficits that lead to HAND. Therefore, we propose to evaluate the efficacy of an adaptive WM computer based training program called Cogmed. Effectiveness of adaptive WM training was shown in children with attention deficit and hyperactivity disorder (ADHD), and in adults with other neurological disorders, but has not been evaluated in HIV-positive subjects. WM deficits also may be related to neuroinflammation, frontal lobe dysfunction or decreased dopaminergic function. Therefore, the aims of this proposal are: 1) To perform a double blind placebo-controlled study using Cogmed to determine whether the intensive adaptive WM training will lead to greater improvement (gain) on WM and other cognitive functions (transfer of gain) in HIV-infected individuals and in HIV-seronegative (SN) controls than fixed low level (placebo) training, at one-month and at six months after training (maintenance of gain). 2) To assess the neural correlates of WM training: Whether brain activation will improve, at 1-month and 6-months after the training, on BOLD-fMRI during WM and attention. 3) Since individuals with the AA genotype for the SNP (rs4657412) for LMX1A showed greater magnitudes of training-related gains in verbal WM in a prior study, we will assess our subjects for this allelic variation on thei training effects (gain and maintenance). Lastly, we will assess changes in neuroinflammatory markers and monoamine metabolites in the CSF of those who consent to lumbar punctures before and 6 months after training, and evaluate the relationships between these CSF makers, cognitive performance and training effects, as well as brain activation fMRI. Although Cogmed is not a cure for HAND, this research project may identify a new and effective adjunctive therapy to improve cognitive function and hence these patients' activities of daily living and functioning. Our genetic study may identify individuals who might benefit the most from the WM training, and therefore help to guide future treatment plans for HIV-infected individuals. Finally, we will also learn how brain activation, neuroinflammation and CSF monoamine levels might relate to WM function before and after the training. PUBLIC HEALTH RELEVANCE: Despite potent combination antiretroviral therapy, cognitive (memory and concentration) problems continue to occur in up to 50% of HIV-infected individuals, especially in older infected individuals, and those who abuse alcohol, marijuana or psychostimulants. Since no effective treatments are available to these individuals with cognitive problems, conservative estimates indicate that the cost of care for these patients could double in the next two decades. To address this urgent problem, this study will use a comprehensive approach (cognitive tests, functional MRI and several biomarkers) to evaluate whether a novel computer-based training program would improve the brain function, especially working memory and attention, in HIV- infected and uninfected individuals.